Implication of heme oxygenase-1 in the sensitivity of nasopharyngeal carcinomas to radiotherapy

High expression of the inducible isoform of heme oxygenase (HO-1) is well known in various solid tumors in human and experimental animal models. To investigate the relationship between HO-1 and nasopharyngeal carcinomas, especially its involvement in the response of nasopharyngeal carcinomas to radiotherapy, thirty-two nasopharyngeal carcinomas were semi-quantitatively analyzed by RT-PCR, and the expression of HO-1 was correlated with the consequence after novel radiotherapy, which was evaluated by the reduction of tumor size. Among 32 nasopharyngeal carcinomas, HO-1 expression was found in19 samples (59.4%), in which 9 patients (47.4%) showed no response to radiotherapy. Interestingly, in 13 nasopharyngeal carcinoma patients with negative expression of HO-1, radiotherapy exhibited to be effective (9 patients, 69.2%) or responsive (3 patients, 23.1%). In this study, we first demonstrated the expression of HO-1 in nasopharyngeal carcinomas, and more important, these findings strongly suggest the potential of HO-1as a useful index in identifying patients with well response to radiotherapy, further these data indicate a new therapeutic for nasopharyngeal carcinoma by inhibiting HO-1 activity, which warrants further investigation

Antitumor effect of PEG-ZnPP in rat glioma cells, F98 and C6, and in rat brainstem tumor models

Objective: Brainstem tumors account for about 10-20% of all primary paediatric tumors in the central nervous system. Approximately 75% of all brainstem tumors in children are diffuse pontine gliomas (DIPG) and the median overall survival is less than a year. Due to its infiltrative character and anatomical location, surgical resection is not considered as therapeutic option. It was described that expression of HO-1 is associated with growth activity of cancer cells, which suggests that a specific inhibitor of HO-1, ZnPP, may work as a potent antitumor therapeutic agent. To evaluate the antitumor efficacy of PEG-ZnPP, a water soluble derivate of ZnPP, we performed studies in vitro and in vivo brainstem glioma models. Methods: To evaluate the antitumor efficacy of PEG-ZnPP in vitro, proliferation assay on glioma cell lines C6 and F98 was performed. Based on the results of our proliferation assay, apoptotic activity using conjugate of annexin V was evaluated and cell cycle analysis was assessed. After in vitro study, we performed systemic therapy with PEG-ZnPP in rat brainstem tumor models with F98 and C6. Neurological status and survival rate was monitored. Results: This project demonstrated that PEG-ZnPP significantly inhibits rat glioma cell proliferation and induces a significant level of apoptosis in C6 and F98 glioma cell lines, suggesting that PEG-ZnPP may represent a potential anticancer agent for brain tumors. In vivo study on rat brainstem glioma models, however, showed no differences of survival between the control group and animals receiving intravenous PEG-ZnPP therapy. Conclusion: In contrast to in vitro studies systemic administration of PEG-ZnPP did not improve the survival on the rat brainstem glioma model suggesting that different approaches and additional animal research are required to overcome the BBB and to further investigate the potential anticancer abilities of PEG-ZnPP.Einleitung: Tumore des Hirnstamms machen ca. 10-20% aller primären Tumoren des zentralen Nervensystems im Kindesalter aus. Zirka 75% aller Tumore im Hirnstamm sind die diffus intrinsischen Ponsgliome (DIPG) und deren mediane Lebenserwartung beträgt weniger als ein Jahr. Aufgrund des infiltrativen Charakters und deren Lokalisation kommt die Resektion als therapeutische Option nicht in Frage. Es ist bekannt, dass erhöhte Expression der HO-1 mit einem raschen Wachstum von Tumorzellen assoziiert ist, sodass eine spezifische Inhibition der HO-1 mittels PEG-ZnPP, eine wasserlösliche Form von ZnPP, als eine anti-tumorale Therapie möglich erscheinen lässt. In dieser Studie wurde antitumorale Wirkung von PEG-ZnPP innerhalb von in vitro Analyse und in vivo im Hirnstammgliom Modell bei der Ratte durchgeführt. Methoden: In der vitro Untersuchung erfolgte zur Evaluation der antitumoren Effektivität eine Proliferationsanalyse in den F98 und C6 Gliomzelllinien. Anschließend erfolgte in einer vivo Studie die Implantation von F98 und C6 Gliomzellen in den Hirnstamm der Ratte gefolgt von einer systemischen Gabe von PEG-ZnPP. Der neurologische Status und das Körpergewicht der Ratte wurden im Verlauf dokumentiert und die Überlebensrate der Tiere bestimmt. Ergebnisse: Diese Studie konnte in den in-vitro Untersuchungen die signifikante Hemmung der Gliomzell-Proliferation durch PEG-ZnPP zeigen. Demgegenüber zeigten die in-vivo Untersuchungen keine Unterschiede der Überlebensrate der PEG-ZnPP behandelten Tiere im Vergleich zu den Kontrolltieren. Schlussfolgerung: Trotz der antitumoralen Wirkung von PEG-ZnPP in vitro zeigte die systemische Applikation im Hirnstammgliom Modell keine überlebensverlängernde Wirkung der Ratte. Am ehesten scheint die Blut-Hirn-Schranke eine relevante Barriere für PEG ZnPP zu sein welches diese Diskrepanz erklären könnte. Als Herausforderung bleibt neue Versuchsverfahren zur Überwindung der Blut-Hirn-Schranke zu finden, um die antitumore Wirksamkeit von PEG-ZnPP in-vivo testen zu können

Heme Oxygenase 1 expression after traumatic brain injury and effect of pharmacological manipulation on functional recovery.

Traumatic Brain Injury (TBI) is an increasingly diagnosed constellation of injuries derived from acute mechanical trauma to the brain. With the rise of advanced neuroimaging techniques recent focus has oriented primarily towards the mild-moderate range of TBI which previously was missed diagnostically. Characteristically, these advances have shown increasing areas of micro-hemorrhage in susceptible areas of the brain and to date there are no treatment modalities targeting micro-hemorrhages or their sequelae. This dissertation explores the effects of the resulting heme processing response in the days following injury with a particular focus on inducing early heme clearance from the parenchyma using a rat central fluid percussion injury model in the mild-moderate injury range. Since heme is released ~24-48 hours post-injury and is known to be cytotoxic we observed there may be a critical window for treatment to clear heme before it is spontaneously released and to increase the buffering capacity of the tissue. We targeted heme clearance by using drugs known to increased expression of Nrf2, an upstream transcriptional regulator of the canonical heme processing protein heme oxygenase 1 (HO-1), and tracking expression of HO-1, the iron sequestration/storage proteins Lipocalin 2 (LCN2) and Ferritin (FTL), as well as the activity of matrix metalloproteinases 2 and 9 (MMP2, MMP9). We examined both tissue known to be frankly hemorrhagic (the neocortex) as well as tissue lacking any identifiable bleed (the hippocampus). We demonstrated that using the HO-1 inducers Hemin and Sulforaphane in a single dose paradigm given 1 hour post-injury heme clearance was accelerated in the neocortex with the majority of heme pigment processed by 24 hours post-injury. Further there was significant attenuation of protein expression in HO-1 and ferritin as well as the enzyme activity of MMP2 and MMP9 in both the neocortex and the hippocampus. Behavioral attenuation was also seen in both rotarod and Morris water maze tests. While we intended to target hemorrhagic processing after injury, and indeed demonstrated improved clearance of heme from post-injury hemorrhagic regions of the brain, in both tissues studied we observed remarkably similar responses to the drugs utilized in protein expression, enzyme activity, and behavioral improvement which may suggest a globally improved pathologic state or that there are unidentified pathologic micro-hemorrhages or leaky vessels which extend further into the brain parenchyma than currently identified

Novel Therapeutic Concepts in Targeting Glioma

Novel Therapeutic Concepts for Targeting Glioma offers a comprehensive collection of current information and the upcoming possibilities for designing new therapies for Glioma by an array of experts ranging from Cell Biologists to Oncologists and Neurosurgeons. A variety of topics cover therapeutic strategies based on Cell Signaling, Gene Therapy, Drug Therapy and Surgical methods providing the reader with a unique opportunity to expand and advance his knowledge of the field